1. Field of the Invention
The present invention relates to the field of methods and compositions for the treatment of hypotension. The invention also relates to the field of combination therapeutic regimens particularly those which include a regimen of a particularly tailored parenteral formulation. The present invention also relates to the field of nitric oxide inhibitors as therapeutic agents in a combination therapeutic regimen.
2. Background of the Related Art
Hypotension, or low blood pressure, is a complicating and often life-threatening condition attendant to shock, traumatic injury, sepsis, the administration of immunomodulators (such as tumor necrosis factor (TNF) for chemotherapy), as well as other situations. Thus, the risk of hypotension affects a significant number of persons throughout the world. For example, septic shock, a potentially lethal complication of bacterial infections, affects 150,000 to 300,000 patients annually in the United States alone..sup.1
The cardiovascular collapse and multiple metabolic derangements associated with septic shock are due largely to bacterial endotoxin (ET), which has been shown to elicit a septic shock-like condition when administered to animals.sup.2. ET is known to stimulate the synthesis and release of several cytokines and biological mediators having hypotensive activity; among the factors released, TNF, platelet activating factor (PAF), prostacyclin and complement-derived C5a anaphylatoxin have been proposed as contributors to the cardiovascular collapse of septic shock.sup.3-6.
Although it has been shown that animals pretreated with anti-TNF antibodies.sup.7, PAF receptor antagonists.sup.8, and prostacyclin synthesis inhibitors.sup.9 may be protected against septic shock, the relative importance of these mediators in the pathology of septic shock is presently uncertain.
There is also evidence that some of these mediators may act indirectly via release of secondary mediators. Thus, the finding that anti-TNF antibodies have little or no protective effect when given after ET exposure.sup.7 suggested to the present inventors that TNF stimulates the production of another factor that is the actual hypotensive agent. Once initiated, synthesis and release of that factor may continue even in the absence of detectable TNF. In 1980, Furchgott et al. (1980).sup.10 demonstrated that endothelial cells, which line blood vessels, can be stimulated to release a substance which relaxes vascular smooth muscle (i.e., causes vasodilatation). Since the chemical nature of this substance was completely unknown, it was simply named endothelium-derived relaxing factor (EDRF). It is hypothesized that many naturally-occurring substances which act as physiological vasodilators mediate all or part of their action by stimulating release of EDRF; these substances include, acetylcholine, histamine, bradykinin, leukotrienes, ADP, ATP, substance P, serotonin, thrombin and others.
The extremely short lifetime of EDRF (several seconds) hampered early efforts to chemically identify this molecule. In 1987, several laboratories suggested that EDRF may be nitric oxide (NO.cndot.), which spontaneously decomposes to nitrate and nitrite..sup.10,11 However, the fundamental problem in accepting this NO.cndot. hypothesis was that mammalian systems were not known to contain an enzymatic pathway which could synthesize NO.cndot.; additionally, a likely precursor for NO.cndot. biosynthesis was unknown.
After observing that the arginine analog L-N.omega.-methylarginine (L-NMA) could inhibit vascular EDRF/NO.cndot. synthesis induced by acetylcholine and histamine, and that EDRF/NO.cndot. synthesis could be restored by adding excess L-arginine, certain of the present inventors proposed that arginine was the physiological precursor of EDRF/NO.cndot. biosynthesis.sup.10. Several of the present inventors later demonstrated that inhibition of EDRF/NO.cndot. synthesis in the anesthetized guinea pig resulted in an increase in blood pressure.
The present inventors have since been able to partially characterize the enzyme responsible for NO.cndot. synthesis. This enzyme has been designated nitric oxide synthase. Nitric oxide synthase is now known to oxidize a terminal nitrogen of the guanidino group of arginine, resulting in production of nitric oxide and citrulline. Macrophage-derived nitric oxide is now considered an important tumoricidal and bactericidal agent.
It has been reported that macrophages become "activated" by 12-36 hour after treatment with gamma-interferon, bacterial endotoxin and various cytokines in vitro. However, this in vitro "activation" system has been associated only with the initiation of tumor cell killing..sup.12 In addition, none of the literature or studies available prior to the present inventors work associated hypotension with nitric oxide. In addition, there currently does not exist definitive evidence of the involvement of macrophages with hypotension.
Macrophages are a quantitatively insignificant component of normal blood vessel walls, and have never been shown to play a role in blood pressure regulation; i.e., there existed no biochemical, physiological or immunological data to suggest that macrophages had any role in pathological hypotension. Thus, the inventors sought to investigate the role of nitric oxide in systems relevant to the manifestation of hypotension, specifically the role of cytokine-induced pathological hypotension, particularly on cells which comprise blood vessel walls.
In both clinical and animal studies on the effects of biological response modifiers, a major dose limiting toxicity has been hypotension and vascular leakage. The inventors have observed that endotoxin and tumor necrosis factor can induce over production of nitric oxide in animals..sup.23,24 Nitric oxide is a vasoactive substance which controls resting blood pressure..sup.13,14 This led the present inventors to postulate that hypotension in humans resulting from administration of biological response modifiers or from the development of overwhelming bacterial infections is due to excessive production of nitric oxide in sufficient concentration to cause excessive loss of systemic vascular resistance. However, macrophages are known to compose quantitatively only an insignificant component of normal blood vessel walls. Moreover, as a practical matter, it was unlikely that the amount of nitric oxide generated by circulating macrophages would be sufficient to elicit a "hypotensive" effect physiologically, as nitric oxide is not produced in vast enough quantities by the limited number of macrophages in blood vessel walls to produce such a pronounced physiological response. This, together with the recognized short half-life nitric oxide in vivo (3-5 seconds), opposed the theory that macrophage-derived nitric oxide was involved in hypotension.
The inventors postulated that: 1) other cell types were possibly linked to pathological hypotension, such as those cells associated with blood vessel walls (endothelial cells and vascular smooth muscle cells); 2) vascular (e.g., endothelial) cells may be stimulated to produce NO.cndot. by stimuli similar to those stimuli found to trigger NO.cndot. generation by macrophage; and 3) septic shock (i.e., systemic vasodilatation induced by bacterial endotoxin) may result from massive activation of NO.cndot. biosynthesis by cells which are a quantitatively significant component of normal blood vessel walls.
The inventors also observed that nitric oxide is derived from the amino acid L-arginine..sup.15 L-arginine is a typical ingredient in commercially available TPN (total parenteral nutrition) formulations.
As hypotension has been observed in patients maintained on standard TPN formulations, a potential valuable improvement in managing the risk of hypotension in these TPN-receiving patients is postulated by the inventors to be provided through a modified TPN formulation which reduces or eliminates the potential synthesis of nitric oxide. As the present inventors have observed that nitric oxide is derived from the amino acid arginine through the action of nitric oxide synthase, the modification of a TPN formulation to reduce or more preferably eliminate the availability of arginine (or the production of dietary arginine) will reduce the production of nitric oxide and the hypotensive effects nitric oxide causes in patients receiving or producing endotoxin, or receiving tumor necrosis factor, or any other of a variety of biological response modifiers. The effects of lowered arginine levels on blood pressure in a hypotensive animal are provided in the inventors prior application, U.S. Ser. No. 767,265, filed Sep. 27, 1991, the Specification of which is specifically incorporated herein by reference and specific reference to herein made.
Interleukin-1-.alpha. (IL-1) has been shown to enhance the restoration of peripheral blood leukocytes in mice myelosuppressed by cytotoxic chemotherapeutic agents..sup.16 In addition, IL-1 inhibits growth of murine tumors in vitro and in vivo and is cytocidal for several tumor cell lines..sup.17,18 Clinical trials in conjunction with the National Cancer Institute are currently underway to assess the efficacy of IL-1 as an immunorestorative agent in cancer patients exhibiting myelosuppression secondary to chemotherapy. In these trials, the does-limiting side effect of IL-1 is hypotension,.sup.19-21 a complication that may prevent the administration of therapeutically effective doses of IL-1.
The association of IL-1 with compromised cardiovascular function is well documented in both animal and patient studies. thus, Dinarello et al..sup.22 have shown that administration of IL-1 causes a shock-like syndrome in rabbits, an effect they attributed to the overproduction of cyclooxygenase products. These authors also have shown a synergistic association between exogenous IL-1 and tumor necrosis factor (TNF) in causing shock. There is now considerable evidence that shock due to exposure to endotoxin (i.e., septic shock) is associated with increased endogenous production of both TNF and IL-1..sup.23 The critical role of IL-1 in endotoxic shock is substantiated by recent reports showing that administration of a human recombinant IL-1 receptor antagonist improves survival.sup.24 and prevents the development of hypotension.sup.25 in rabbits given endotoxin.
The inventors have previously shown that pathologic overproduction of nitric oxide (NO.cndot.)--initially characterized as endothelium-derived relaxing factor.sup.10,11 --mediates the hypotension caused by the administration of TNF to dogs..sup.26 This data has also been described in the inventors patent application U.S. Ser. No. 406,909, filed Sep. 13, 1989, now U.S. Pat. No. 5,028,627, the Specification of which is specifically incorporated herein by reference. U.S. Ser. No. 838,814 filed Mar. 13, 1992 by the present inventors, is a continuation application of U.S. Pat. No. 5,028,627. The present disclosure is a continuation of U.S. Ser. No. 838,814. U.S. Ser. No. 838,814, is specifically referred to herein for purposes of establishing a continuous chain of copendency with the present application.
NO.cndot. is a short-lived but potent vasodilator formed enzymatically by oxidation of one of the two equivalent guanidino (i.e., omega) nitrogens of L-arginine in a reaction catalyzed by nitric oxide synthase..sup.27,28 Several N.sup..omega. -substituted arginine analogues are effective inhibitors of nitric oxide synthase,.sup.29-33 and some have been shown to inhibit NO.cndot. production in vivo.
Some of these N.sup..omega. -substituted arginine analogs include N.sup..omega. -methyl-L-arginine (NMA), NNA (N.sup..omega. -nitro-L-arginine) and NAA (N.sup..sup..omega. -amino-L-arginine). Some enthusiasm has been generated in regard to the use of nitric oxide inhibitors, such as NMA, as antihypotensive agents. However, this prospect has been tempered by the recent demonstration that very large doses of NMA demonstrates an increase in mortality in endotoxic rodents,.sup.34 while other studies have indicated that NMA increases hepatic damage following administration of endotoxin to rats..sup.35 The inventors own work has also shown that treatment with large doses of arginine analogs, such as NMA results in lower cardiac output in vivo while increasing blood pressure, the results of which could compromise oxygen delivery to critical organs. Therefore, methods and regimens which could optimize the potential normotensive action of these agents at lower doses would make these agents significantly more acceptable and useful in the clinical setting.
A method which would maximize the beneficial anti-hypotensive effects of low physiological arginine concentrations, for example, by the maintenance of an animal, on an arginine-free dietary support (TPN), coupled with moderate doses of a nitric oxide synthase inhibitor would provide a significant advantage in managing an animal with hypotension or at risk of developing hypotension.